The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted to recommend approval of lorcaserin (Lorqess, Arena). The result signals a remarkable turnaround for the drug, which the same panel had rejected in September 2010. The vote was 18 in favor of approval, 4 against, and 1 abstention.

Committee members seemed less disturbed this time around about the issues that concerned them at the earlier meeting. The theoretical risk of an increase in cancer was discussed at length but did not appear to bother the panel. Valvulopathy and cardiovascular adverse events were the major obstacles. For valvulopathy, although the data from Arena did not allow the FDA reviewers to rule out an increased relative risk of 1.5 with lorcaserin, the absolute incidence of valve problems was low. A few panel members raised the idea of requiring echocardiograms prior to prescribing lorcaserin.

An increased risk of cardiovascular adverse events could not be ruled out by the committee, but members felt that it would be unfair to change the rules in midstream and require a CV events study prior to approval. It appears likely that the FDA will require a post-approval outcomes study if the drug is approved, however.

Committee members wrestled for much of the day with questions about the drug’s modest efficacy in producing weight loss, a problem that was exacerbated by the high rate of dropouts in clinical trials. Ultimately, however, Arena was able to demonstrate that the drug met one of the predefined FDA criteria for efficacy.

Sanjay Kaul, a panel member who was one of the four negative votes, provided the following comment:

There is a discernible weight loss with lorcaserin which meets the categorical weight loss efficacy criterion outlined by the FDA draft guidance. However, this is a necessary, but not sufficient, criterion, in my opinion. The weight loss did not translate into a tangible benefit in clinically relevant cardiometabolic biomarkers, quality of life, or risk prediction models except for improvement in HbA1c in the cohort with type 2 diabetes mellitus (less than 8% of the overall development program).

There remains lingering uncertainty regarding potential valvulopathy associated with lorcaserin as the sponsor failed to rule out the prespecified excessive FDA-defined VHD risk. I had no issues with cancer or neuropsychiatric adverse events, and there was insufficient evidence to assess MACE risk.

Benefit-risk assessment is essentially a qualitative science grounded in quantitative data and dependent upon judgment. Using this framework, the totality of evidence does not persuade me to conclude that the potential benefits of lorcaserin outweigh the potential risks when used long-term in a population of overweight and obese individuals.